Discovery of CO 2 tolerance genes associated with virulence in the fungal pathogen Cryptococcus neoformans.

Cryptococcus neoformans is a ubiquitous soil fungus and airborne pathogen that causes over 180,000 deaths each year. Cryptococcus must adapt to host CO 2 levels to cause disease, but the genetic basis for this adaptation is unknown. We utilized quantitative trait loci mapping with 374 progeny from a cross between a CO 2 -tolerant clinical isolate and a CO 2 -sensitive environmental isolate to identify genetic regions regulating CO 2 tolerance. To identify specific quantitative trait genes, we applied fine mapping through bulk segregant analysis of near-isogenic progeny with distinct tolerance levels to CO 2 . We found that virulence among near-isogenic strains in a murine model of cryptococcosis correlated with CO 2 tolerance. Moreover, we discovered that sensitive strains may adapt in vivo to become more CO 2 tolerant and more virulent. These findings highlight the underappreciated role of CO 2 tolerance and its importance in the ability of an opportunistic environmental pathogen to cause disease.